Clopidogrel, an inhibitor of induced platelet aggregation, is the dextro-rotatory enantiomer of methyl-alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)-(2-chlorophenyl)-acetate, having the absolute configuration S and is represented by Formula (I).

U.S. Pat. No. 4,529,596 provides Methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate.
U.S. Pat. No. 4,847,265 (herein after “the '265 patent”) provides the dextro-rotatory enantiomer of methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate and a pharmaceutically acceptable salts thereof. The hydrochloride, hydrogen sulfate, hydrobromide and taurocholate salts are specifically provided.
The '265 patent provides a process to obtain salts of methyl S-(+)-alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate, wherein racemic methyl-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate (Formula II) is resolved by 0.399 mole equivalent of laevorotatory camphor-10-sulfonic acid monohydrate (with respect to methyl alpha-5-(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2-chlorophenyl)-acetate) to give methyl (R)-(−)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (Formula IV), which remains in the mother liquor and can be converted in to methyl (R)-(−)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate by known methods, whereupon methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (Formula III) separates out after a long period of crystallisation (72 hours) as a solid in very low yield [55% w/w and 31.94%] as shown in Scheme 1.

PCT Patent Publication No. WO 98/51689 provides the process of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate in example 22 by using 0.39 mole equivalent of laevorotatory camphor-10-sulfonic acid monohydrate (with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate) whereupon methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (Formula III) separates out after a long period of crystallisation (72 hours) as a solid in 88% yield, which is not possible even theoretically as the process involves the use of only 0.39 mole equivalent of laevorotatory camphor-10-sulfonic acid monohydrate with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate.
PCT Patent Publication No. WO 2004/013147 provides a process of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate by using 0.6 mole equivalent to 0.8 mole equivalent of laevorotatory camphor-10-sulfonic acid (with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate). However, the patent does not provide the yield of methyl (S)-(+)-alpha-(2-chlorophenyl) -6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt.
U.S. Pat. No. 6,504,030 provides a process of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate by using 0.6 mole equivalent of laevorotatory camphor-10-sulfonic acid (with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate), whereupon methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (Formula III) separates out as a solid in 33% yield by crystallisation. However, the patent does not describe the time of crystallisation.
U.S. Pat. No. 6,635,763 provides a process of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate in example 54, by using 1 mole equivalent of laevorotatory camphor-10-sulfonic acid (with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate), whereupon methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (III) separates out as a solid in 36% yield by crystallisation. However, the patent does not provide the time required for crystallisation.
U.S. Patent Application No. 2005/059696 provides the process of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate in example 7 by using 1 mole equivalent of laevorotatory camphor-10-sulfonic acid (with respect to methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate), whereupon methyl (S)-(+)-alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate camphor sulfonic acid salt (III) separates out as a solid in 30.23% yield by crystallisation for 20 hours.
The problem with the preparation of clopidogrel and its pharmaceutically acceptable salts thereof is the low yield obtained in the step of resolving methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate by the salt formation with levorotatory camphor-10-sulfonic acid, which increases the overall production cost of clopidogrel and its pharmaceutically acceptable salts thereof.
Accordingly, an inexpensive and commercially viable process to prepare clopidogrel and pharmaceutically acceptable salts thereof is required.